Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β 1-integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding

Int J Mol Sci. 2020 Jul 13;21(14):4956. doi: 10.3390/ijms21144956.

Abstract

Collagen type 1 (COL1) is a ubiquitously existing extracellular matrix protein whose high density in breast tissue favors metastasis and chemoresistance. COL1-binding of MDA-MB-231 and MCF-7 breast cancer cells is mainly dependent on β1-integrins (ITGB1). Here, we elucidate the signaling of chemoresistance in both cell lines and their ITGB1-knockdown mutants and elucidated MAPK pathway to be strongly upregulated upon COL1 binding. Notably, Discoidin Domain Receptor 1 (DDR1) was identified as another important COL1-sensor, which is permanently active but takes over the role of COL1-receptor maintaining MAPK activation in ITGB1-knockdown cells. Consequently, inhibition of DDR1 and ERK1/2 act synergistically, and sensitize the cells for cytostatic treatments using mitoxantrone, or doxorubicin, which was associated with an impaired ABCG2 drug efflux transporter activity. These data favor DDR1 as a promising target for cancer cell sensitization, most likely in combination with MAPK pathway inhibitors to circumvent COL1 induced transporter resistance axis. Since ITGB1-knockdown also induces upregulation of pEGFR in MDA-MB-231 cells, inhibitory approaches including EGFR inhibitors, such as gefitinib appear promising for pharmacological interference. These findings provide evidence for the highly dynamic adaptation of breast cancer cells in maintaining matrix binding to circumvent cytotoxicity and highlight DDR1 signaling as a target for sensitization approaches.

Keywords: ABC transporter; DDR1; EGFR; MAPK; breast cancer; chemoresistance; collagen; integrin.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism
  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Biological Transport / drug effects
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Collagen Type I / metabolism*
  • Discoidin Domain Receptor 1 / antagonists & inhibitors
  • Discoidin Domain Receptor 1 / physiology*
  • Doxorubicin / metabolism
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / physiology
  • ErbB Receptors / biosynthesis
  • ErbB Receptors / genetics
  • Focal Adhesion Kinase 1 / metabolism
  • Gefitinib / pharmacology
  • Gefitinib / therapeutic use
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Indazoles / pharmacology
  • Integrin beta1 / genetics
  • Integrin beta1 / physiology*
  • Integrin beta4 / biosynthesis
  • Integrin beta4 / genetics
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • MCF-7 Cells
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
  • Mitoxantrone / metabolism
  • Mitoxantrone / pharmacology
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / metabolism
  • Neoplasm Proteins / physiology*
  • Piperazines / pharmacology
  • Tumor Microenvironment / drug effects

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Collagen Type I
  • ITGB4 protein, human
  • Indazoles
  • Integrin beta1
  • Integrin beta4
  • Itgb1 protein, human
  • Neoplasm Proteins
  • Piperazines
  • SCH772984
  • Doxorubicin
  • Mitoxantrone
  • DDR1 protein, human
  • Discoidin Domain Receptor 1
  • EGFR protein, human
  • ErbB Receptors
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • MAPK1 protein, human
  • MAPK3 protein, human
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Gefitinib